We seek to generate and characterize a novel model of tauopathy to evaluate whether enhancing site-specific tau acetylation can combat the aberrant accumulation of tau protein driving neurodegeneration in tauopathies such as Frontotemporal dementia (FTD). Efforts to elucidate pathogenic mechanisms and assess the efficacy of various therapeutic targets are limited by existing models of tauopathy. To address this unmet need, we recently developed a novel model of tauopathy that closely mimics the behavioral phenotypes observed in transgenic models of tauopathy with the added benefit of recapitulating classic features of pathological tau lesions in humans. Utilizing somatic brain transgenesis to deliver adeno-associated virus (AAV) encoding human mutant P301L-tau, we developed a model in which both straight and twisted tau filaments - hallmark features of neurofibrillary tangles (NFTs) - are accurately preserved. In the current project, we seek to further define how manipulating the pattern of posttranslational modifications on tau's KXGS motifs influences tauopathy in vivo. Our team has successfully demonstrated a very dynamic and competitive relationship exists between tau acetylation and phosphorylation on KXGS motifs, with loss of acetylation and increased hyperphosphorylation leading to disease. As such, we hypothesize that strategies to enhance acetylation of KXGS motifs will prevent tau hyperphosphorylation and recruitment to NFTs and slow disease progression in a novel, AAV-based model of tauopathy. As histone deacetylase 6 (HDAC6) can also adjust the balance between acetylation and phosphorylation on these motifs, we will monitor the progression of tauopathy in P301L-AAV-injected mice lacking the HDAC6 gene to determine whether favoring acetylation is protective in the context of tauopathy. We anticipate that upon completion of the following aims, we will not only provide the field with a well-characterized model of tauopathy that can be easily and cost-effectively reproduced and distributed, but we will also provide novel insight into the mechanism(s) by which acetylation/phosphorylation and HDAC6 regulate tau proteotoxicity.